This is a continuing Program Project, currently in year 10, to identify cellular and molecular mechanisms of hypoxic-ischemic brain injury. Research in the previous funding periods centered on excitotoxic neuron-neuron and neuron-glial interactions. The current proposal expands this scope to include the role of vascular injury and inflammation. There is growing recognition that approaches to reducing ischemic brain injury must also protect the "neurovascular unit," comprised of blood, microvascular endothelium, astrocytes, and blood-brain barrier, together with the surrounding neuroglial parenchyma. Ten closely interacting faculty investigators will pursue new directions in three research projects. In Project 1, "Ischemic tolerance and endothelial protection," Jeff Gidday will explore microvascular mechanisms underlying ischemic tolerance using cerebral endothelial cultures and a new mouse model in which repetitive hypoxic preconditioning promotes protection sustained over weeks. Stroke and other disorders of the neurovascular unit affect cerebral white matter, and in Project 2, "Mechanisms of axon injury in ischemic white matter," Mark Goldberg will use lentivirus vectors directing expression of molecular inhibitors to identify downstream pathways of axon degeneration. In Project 3, "Pathogenesis of CAA-induced vascular dysfunction," David Holtzman and Hans Dietrich will use in vivo and in situ approaches to examine effects of cerebral amyloid angiopathy on arteriolar function, an emerging cause of ischemic and hemorrhagic stroke in the elderly. These projects will be supported by the following Cores: Core A: "Administrative and statistical core", Core B: "Animal models", Core C: "Molecular neurosciences / viral vectors", and Core D: "Microscopy." The investigators share experimental approaches including in vivo and in vitro models, expertise in advanced microscopy, and a common interest in identifying new therapeutic approaches to stroke. RELEVANCE FOR PUBLIC HEALTH: Approximately 700,000 Americans experience a stroke each year. This project examines mechanisms of brain injury in stroke. The long-term goal of this project is to identify potential new forms of therapy to reduce injury and promote recovery in stroke.